PROJECT SUMMARY Hepatic dysfunction or failure caused by ischemia-reperfusion injury (IRI) is a major problem following liver transplantation, resection, and the hemorrhagic shock. Despite recent progress in improving surgical procedure and pharmacological therapy, the host immune response leading to liver damage remains the greatest challenge during hepatic IR. Embryonic stem (ES) cell derivatives offer a potentially important renewable source of any type of tissue for cell replacement therapies. Dendritic cells (DC) are specialized immune cells that play vital roles in initiating robust immunity against pathogens as well as maintaining immune homeostasis. The regulation of liver inflammatory response using genetically modified ES cell-derived DC (ES- DC) could potentially ameliorate liver damage. Recently, it has been shown that ?-catenin is required for the regulation of immune response induced by DC, critical for the innate and adaptive immunity in inflammatory disease. Moreover, Notch signaling is essential for the DC differentiation and function. The overall goal of this proposal is to elucidate the roles and potential mechanisms of ?-catenin in regulating immune response in ES- DC, and the acquisition of immune regulation in hepatic IRI by an inducible ?-catenin-modified ES cell system. We hypothesize that induction of ?-catenin activity in ES-DC regulates IR-triggered inflammatory response in liver via a Notch-mediated Jagged1-Hes1 signaling network. To test this hypothesis, the following specific aims are proposed: 1) Investigate the role of ?-catenin in regulating immune response in ES- DC. 2) Investigate the acquisition of immune regulation by ?-catenin-modified ES-DC in vivo. These studies will reveal the role of ?-catenin in controlling ES-DC function and increase our understanding of ?-catenin- mediated immunoregulatory networks in innate and adaptive immune system during IR-triggered liver inflammation. Using genetically modified ES-DC system provides a novel approach and establishes a potential clinical feasibility for the amelioration of ischemic tissue injury in organ transplantation, resection, and hemorrhagic shock, as well as other sterile inflammatory disease states.